Fused bicyclic diamine derivatives as hiv attachment inhibitors

ABSTRACT

Compounds of Formula I, including pharmaceutically acceptable salts thereof: 
     
       
         
         
             
             
         
       
     
     wherein A is selected from the group of: 
     
       
         
         
             
             
         
       
     
     are useful as HIV attachment inhibitors.

CROSS REFERENCE TO RELATED APPLICATION

This non-provisional application claims the benefit of U.S. ProvisionalApplication Ser. No. 61/528,382 filed Aug. 29, 2011.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Inparticular, the invention herein is directed to fused bicyclic diaminederivatives as HIV attachment inhibitors that possess unique antiviralactivity.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 50 million people infected worldwide at theend of 2010. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors zidovudine (or AZT orRETROVIR®), didanosine (or VIDEX®), stavudine (or ZERIT®), lamivudine(or 3TC or EPIVIR®), zalcitabine (or DDC or HIVID®), abacavir succinate(or ZIAGEN®), tenofovir disoproxil fumarate salt (or VIREAD®),emtricitabine (or FTC-EMTRIVA®); non-nucleoside reverse transcriptaseinhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®),efavirenz (or SUSTIVA®), etravirine (INTELENCE®) and rilpivirine(EDURANT®), and peptidomimetic protease inhibitors or approvedformulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir,lopinavir, KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir(REYATAZ®) and tipranavir (APTIVUS®), and integrase inhibitors such asraltegravir (ISENTRESS®), and entry inhibitors such as enfuvirtide(T-20) (FUZEON®) and maraviroc (SELZENTRY®). Several single pillcombinations have been also approved, which include COMBIVIR® (containslamivudine and zidovudine), TRIZIVIR® (contains abacavir, zidovudine,and lamivudine), Epzicom (contains abacavir and lamivudine), TRUVADA®(contains tenofovir disoproxil fumarate and emtricitabine), ATRIPLA®(contains efavirenz, emtricitabine and tenofovir disoproxil fumarate)and COMPLERA® (contains emtricitabine, rilpivirine, and tenofovirdisoproxil fumarate).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been recentlydocumented as a consequence of the widespread application of combinationtherapy. However, despite these impressive results, 30 to 50% ofpatients may ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g., mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present. Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options. Improved HIV fusion inhibitors and HIV entrycoreceptor antagonists are two examples of new classes of anti-HIVagents further being studied by a number of investigators.

HIV attachment inhibitors are a novel subclass of antiviral compoundsthat bind to the HIV surface glycoprotein gp120, and interfere with theinteraction between the surface protein gp120 and the host cell receptorCD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, andblock HIV replication in the first stage of the HIV life cycle. Theproperties of HIV attachment inhibitors have been improved in an effortto obtain compounds with maximized utility and efficacy as antiviralagents. A disclosure describing indoles of which the structure shownbelow for BMS-705 is representative, has been disclosed (AntiviralIndoleoxoacetyl piperazine Derivatives).

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials has beendisclosed in the literature.

It should be noted that in all three of these structures, a piperazineamide (in these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such efforts include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substitutedheteroaromatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo 4.4.0 antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline-containing compounds.

Method(s) for preparing prodrugs for this class of compounds aredisclosed in Prodrugs of piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. Publication No. 2005/0209246 or WO 2005/090367A1).

A published PCT patent application WO 2003/103607 A1 (Jun. 11, 2003)disclosures an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, U.S. Publication No.2005/0215543 (WO 2005/102328 A1), U.S. Publication No. 2005/0215544 (WO2005/102391 A1), and U.S. Publication No. 2005/0215545 (WO 2005/102392A2).

A publication on new compounds in this class of attachment inhibitors(Wang, J. et al., Org. Biol. Chem., 3:1781-1786 (2005)) and a patentapplication on some more remotely related compounds have appeared in WO2005/016344, published on Feb. 24, 2005.

Published patent applications WO 2005/016344 and WO 2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. Otherreferences in the HIV attachment area include U.S. Publication Nos.2007/0155702, 2007/0078141 and 2007/0287712, WO 2007/103456, as well asU.S. Pat. Nos. 7,348,337 and 7,354,924. A literature reference is J.Med. Chem., 50:6535 (2007).

What is therefore needed in the art are new HIV attachment inhibitorcompounds, and compositions thereof, which are efficacious against HIVinfection.

Of particular interest are new fused bicyclic diamines as HIV attachmentinhibitor compounds, described herein. The compounds of the presentinvention are fused bicyclic diamine derivatives, which are structurallydistinct from the piperazine HIV attachment inhibitors disclosed inliterature.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvates areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound ofFormula I, including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷,XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group F; wherein aryl is napthyl orsubstituted phenyl; wherein heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for a mono cyclic system and up to12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which maycontain from 1 to 2 heteroatoms in the ring skeleton and which may befused to a benzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from the group consistingof C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)₂-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁷ is selected from the group consisting of aryl, heteroaryl, andheteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of(a) hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with oneto three same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryland (C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or they can conjointo form a ring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide and steroid, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic;K is selected from the group of

P is selected form Ar or J;Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are each independently optionallysubstituted with one to three same or different members selected fromthe group Ar—I; and heteroaryl is selected from the group consisting ofpyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;Ar—I is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, primary amine, secondary amine, tertiaryamine, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone,amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, oxime andhydrazine, among which ether, thioether, secondary amine, tertiaryamine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can beeither acyclic or cyclic; wherein said (C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl is optionally substituted with one to three same ordifferent of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, oxime and hydrazine, among which ether, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic;J is selected from the group consisting of H, C₁-C₃₀ alkyl, C₃-C₃₀cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl,aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine,C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether,C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide,C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclicsulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea,C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀guanidine, and C₃-C₃₀ cyclic guanidine; aryl or heteroaryl is selectedfrom the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl,oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl,triazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl,indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl,azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein saidC₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀tetracycloalkyl, phenyl, aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acylsulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀ cyclic guanidine isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,and peroxide, among which ether, peroxide, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic;Z is selected from the group consisting of phenyl, C₅-C₇ monocyclicheteroaryl, C₉-C₁₀ bicyclic aryl, C₉-C₁₀ bicyclic heteroaryl, C₄-C₇heteroalicyclic, and C₅-C₇ cycloalkyl wherein said heteroaryl orheteroalicyclic contains from 1 to 4 heteroatoms selected from O, N, andS and with the proviso when Z is a bicyclic heteroaryl both R and Z areattached to a common ring wherein said aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from oxo, hydroxyl, C₁-C₆alkyl, —NR¹⁰¹R¹⁰², —OC₁—C₃ alkyl,—S—R_(1,)—S(O)₂R_(1,) CF_(3,) CN; wherein said C₁-C₆ alkyl can beoptionally substituted with Group B;I₁, I₂, I₃, I₄, I₅, I₆, I₇, I₈, I₉, and I₁₀ are each independentlyselected from the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl,(C₂₋₆) alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR⁸¹R⁸²OR⁸³, COR⁸⁴,COOR⁸⁵, or CONR⁸⁶R⁸⁷; wherein each of said alkyl and cycloalkyl beingoptionally substituted with one to three same or different cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, and R⁸⁷ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl; and whereinR¹⁰¹ and R¹⁰² are selected from the group consisting of H, C₁-C₃₀ alkyl,C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl,aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine,C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether,C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide,C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclicsulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea,C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀guanidine, and C₃-C₃₀ cyclic guanidine; aryl or heteroaryl is selectedfrom the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl,oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl,triazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl,indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl,azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein saidC₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀tetracycloalkyl, phenyl, aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acylsulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀ cyclic guanidine isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,and peroxide, among which ether, peroxide, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic.

Another embodiment of the present invention is directed to a method fortreating mammals infected with a virus, especially wherein the virus isHIV, comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I above, and one or morepharmaceutically acceptable carriers, excipients or diluents.Optionally, the compound of Formula I can be administered in combinationwith an antiviral effective amount of an AIDS treatment agent selectedfrom the group consisting of: (a) an AIDS antiviral agent; (b) ananti-infective agent; (c) an immunomodulator; and (d) other HIV entryinhibitors.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or moremethods for making the compounds of Formula I.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds of the present invention may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

Unless otherwise specifically set forth elsewhere in the application,one or more of the following terms may be used herein, and shall havethe following meanings:

The term “H” refers to hydrogen, including its isotopes, such asdeuterium.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄ fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” or “Ar” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encompass systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroalicyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this disclosure. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfuric acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g., hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

As stated above, the compounds of the invention also include “prodrugs”.The term “prodrug” as used herein encompasses both the term “prodrugesters” and the term “prodrug ethers”. The term “prodrug esters” asemployed herein includes esters and carbonates formed by reacting one ormore hydroxyls of compounds of Formula I with either alkyl, alkoxy, oraryl substituted acylating agents or phosphorylating agent employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, amino acid esters, phosphates,half acid esters such as malonates, succinates or glutarates, and thelike. In certain embodiments, amino acid esters may be especiallypreferred.

Examples of such prodrug esters include

The term “prodrug ethers” include both phosphate acetals andO-glucosides. Representative examples of such prodrug ethers include

Prodrug derivatives in which the prodrug moiety is attached to theindole N atom are also considered part of this invention. These prodrugscan be prepared by substitution of the indole N with a moiety thatmodifies the physical properties of the compound and can be unmaskedeither by chemical or enzymatic degradation. Examples of R₃ include acylderivatives similar to those described above. A preferred prodrug is thephosphonoxymethyl moiety which can be introduced using methodspreviously described and converted to pharmaceutically acceptable saltforms that confer chemical stability and advantageous physicalproperties:

As set forth above, the invention is directed to compounds of Formula I,including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷,XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹,(C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl, and heteroalicyclicare optionally substituted with one to three same or different halogensor from one to three same or different substituents selected from thegroup F; wherein aryl is napthyl or substituted phenyl; whereinheteroaryl is a mono or bicyclic system which contains from 3 to 7 ringatoms for a mono cyclic system and up to 12 atoms in a fused bicyclicsystem, including from 1 to 4 heteroatoms; wherein heteroalicyclic is a3 to 7 membered mono cyclic ring which may contain from 1 to 2heteroatoms in the ring skeleton and which may be fused to a benzene orpyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from the group consistingof C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁷ is selected from the group consisting of aryl, heteroaryl, andheteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic areoptionally substituted with one to three same or different halogens orwith from one to three same or different substituents selected from thegroup F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of (a)hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryland (C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO2D¹, SO2ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or they can conjointo form a ring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide and steroid, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic;K is selected from the group of

P is selected form Ar or J;Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are each independently optionallysubstituted with one to three same or different members selected fromthe group Ar—I; and heteroaryl is selected from the group consisting ofpyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;Ar—I is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, primary amine, secondary amine, tertiaryamine, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone,amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, oxime andhydrazine, among which ether, thioether, secondary amine, tertiaryamine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can beeither acyclic or cyclic; wherein said (C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl is optionally substituted with one to three same ordifferent of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, oxime and hydrazine, among which ether, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic;J is selected from the group consisting of H, C₁-C₃₀ alkyl, C₃-C₃₀cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl,aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine,C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether,C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide,C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclicsulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea,C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀guanidine, and C₃-C₃₀ cyclic guanidine; aryl or heteroaryl is selectedfrom the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl,oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl,triazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl,indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl,azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein saidC₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀tetracycloalkyl, phenyl, aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acylsulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀ cyclic guanidine isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,and peroxide, among which ether, peroxide, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic;Z is selected from the group consisting of phenyl, C₅-C₇ monocyclicheteroaryl, C₉-C₁₀ bicyclic aryl, C₉-C₁₀ bicyclic heteroaryl, C₄-C₇heteroalicyclic, and C₅-C₇ cycloalkyl wherein said heteroaryl orheteroalicyclic contains from 1 to 4 heteroatoms selected from O, N, andS and with the proviso when Z is a bicyclic heteroaryl both R and Z areattached to a common ring wherein said aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from oxo, hydroxyl, C₁-C₆ alkyl, —NR¹⁰¹R¹⁰², —OC₁-C₃ alkyl,—S—R_(1,)—S(O)₂R_(1,) CF_(3,) CN; wherein said C₁-C₆ alkyl can beoptionally substituted with Group B;I₁, I₂, I₃, I₄, I₅, I₆, I₇, I₈, I₉, and I₁₀ are each independentlyselected from the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl,(C₂₋₆) alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR⁸¹R⁸²OR⁸³, COR⁸⁴,COOR⁸⁵, or CONR⁸⁶R⁸⁷; wherein each of said alkyl and cycloalkyl beingoptionally substituted with one to three same or different cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;R⁸¹, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, and R⁸⁷ are each independently selectedfrom the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆)alkenyl, (C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl; and whereinR¹⁰¹ and R¹⁰² are selected from the group consisting of H, C₁-C₃₀ alkyl,C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl,aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine,C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether,C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide,C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclicsulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea,C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀guanidine, and C₃-C₃₀ cyclic guanidine; aryl or heteroaryl is selectedfrom the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl,oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl,triazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl,indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl,azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein saidC₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀tetracycloalkyl, phenyl, aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acylsulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀ cyclic guanidine isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,and peroxide, among which ether, peroxide, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic.

In a further embodiment of Formula I above, there is the proviso that atleast one of a-e is selected from B or E.

Also preferred are compounds wherein A is

More preferred compounds of Formula I include those which are selectedfrom:

including pharmaceutically acceptable salts thereof.

Of these, the following compounds are even more preferred:

including

pharmaceutically acceptable salts thereof.

The compounds of the present invention, according to all the variousembodiments described above, may be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, and by other means, in dosage unit formulations containingnon-toxic pharmaceutically acceptable carriers, excipients and diluentsavailable to the skilled artisan. One or more adjuvants may also beincluded.

Thus, in accordance with the present disclosure, there is furtherprovided a method of treatment, and a pharmaceutical composition, fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition which contains an antiviral effective amountof one or more of the compounds of Formula I, together with one or morepharmaceutically acceptable carriers, excipients or diluents. As usedherein, the term “antiviral effective amount” means the total amount ofeach active component of the composition and method that is sufficientto show a meaningful patient benefit, i.e., inhibiting, ameliorating, orhealing of acute conditions characterized by inhibition of the HIVinfection. When applied to an individual active ingredient, administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously. The terms “treat, treating,treatment” as used herein and in the claims means preventing,ameliorating or healing diseases associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form oforally administrable suspensions or tablets; as well as nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions or suppositories. Pharmaceuticallyacceptable carriers, excipients or diluents may be utilized in thepharmaceutical compositions, and are those utilized in the art ofpharmaceutical preparations.

When administered orally as a suspension, these compositions areprepared according to techniques typically known in the art ofpharmaceutical formulation and may contain microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners/flavoringagents known in the art. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents, and lubricantsknown in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses, usuallyover an extended period, such as days, weeks, months, or even years. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula Iherein set forth, together with one or more agents useful in thetreatment of AIDS. For example, the compounds of this disclosure may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines, such asthose in the following non-limiting table:

ANTIVIRALS Drug Name Manufacturer Indication Rilpivirine Tibotec HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Complera ® Gilead HIV infection, AIDS, ARC; combination withemtricitabine, rilpivirine, and tenofovir disoproxil fumarate 097Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse tran-scriptase (RT) inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) AcemannanCarrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-234475 Bristol-MyersSquibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (proteaseinhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir GileadScience CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI PharmaUSA HIV infection Cytomegalovirus MedImmune CMV retinitis Immune globinCytovene Syntex Sight threatening Ganciclovir CMV peripheral CMVretinitis Darunavir Tibotec- J & J HIV infection, AIDS, ARC (proteaseinhibitor) Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RTinhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd.(Osaka, positive Japan) asymptomatic ddC Hoffman-La Roche HIV infection,AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS,Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection,(Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz Bristol MyersSquibb HIV infection, (DMP 266, Sustiva ®) AIDS, ARC (−)6-Chloro-4-(S)-(non-nucleoside RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp,PLC HIV infection (Gainesville, GA) Etravirine Tibotec/J & J HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Famciclovir Smith Kline herpes zoster, herpes simplex GS 840 Gilead HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion HIV infection, Roussel AIDS, ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC,AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersSquibb CMV infection Nelfinavir Agouron HIV infection, PharmaceuticalsAIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection,Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIVinhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide(Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIVPhosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC Thymidine TipranavirBoehringer Ingelheim HIV infection, AIDS, ARC (protease inhibitor)Valaciclovir Glaxo Wellcome Genital HSV & CMV Infections VirazoleViratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS,ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRocheHIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies Tenofovir disoproxil, Gilead HIV infection, fumarate salt(Viread ®) AIDS, (reverse transcriptase inhibitor) Emtriva ®(Emtricitabine) Gilead HIV infection, (FTC) AIDS, (reverse transcriptaseinhibitor) Combivir ® GSK HIV infection, AIDS, (reverse transcriptaseinhibitor) Abacavir succinate GSK HIV infection, (or Ziagen ®) AIDS,(reverse transcriptase inhibitor) Reyataz ® Bristol-Myers Squibb HIVinfection (or atazanavir) AIDs, protease inhibitor Fuzeon ®Roche/Trimeris HIV infection (Enfuvirtide or T-20) AIDs, viral Fusioninhibitor Lexiva ® GSK/Vertex HIV infection (or Fosamprenavir calcium)AIDs, viral protease inhibitor Selzentry Pfizer HIV infection Maraviroc;(UK 427857) AIDs, (CCR5 antagonist, in development) Trizivir ® GSK HIVinfection AIDs, (three drug combination) Sch-417690 (vicriviroc)Schering-Plough HIV infection AIDs, (CCR5 antagonist, in development)TAK-652 Takeda HIV infection AIDs, (CCR5 antagonist, in development) GSK873140 GSK/ONO HIV infection (ONO-4128) AIDs, (CCR5 antagonist, indevelopment) Integrase Inhibitor Merck HIV infection MK-0518 AIDsRaltegravir Truvada ® Gilead Combination of Tenofovir disoproxilfumarate salt (Viread ®) and Emtriva ® (Emtricitabine) IntegraseInhibitor Gilead/Japan Tobacco HIV Infection GS917/JTK-303 AIDsElvitegravir in development Triple drug combination Gilead/Bristol-MyersSquibb Combination of Tenofovir Atripla ® disoproxil fumarate salt(Viread ®), Emtriva ® (Emtricitabine), and Sustiva ® (Efavirenz)Festinavir ® Oncolys BioPharma HIV infection AIDs in development CMX-157Chimerix HIV infection Lipid conjugate of AIDs nucleotide tenofovir

IMMUNOMODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-AyerstAIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan CarringtonLabs, Inc. AIDS, ARC (Irving, TX) CL246, 738 Wyeth AIDS, Kaposi'sLederle Labs sarcoma FP-21399 Fuki ImmunoPharm Blocks HIV fusion withCD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumornecrosis factor) Granulocyte Genetics Institute AIDS Macrophage ColonySandoz Stimulating Factor Granulocyte Hoechst-Roussel AIDS MacrophageColony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS,Macrophage Colony combination Stimulating Factor w/AZT HIV Core ParticleRorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inInterleukin-2 CD4 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon

ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin withPharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcalmeningitis, candidiasis Pastille Squibb Corp. Prevention of NystatinPastille oral candidiasis Ornidyl Merrell Dow PCP EflornithinePentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL)Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial PiritreximBurroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCPprophylaxis Isethionate for Inhalation Spiramycin Rhone-PoulencCryptosporidial diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis;R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCPDaunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human OrthoPharm. Corp. Severe anemia Erythropoietin assoc. with AZT therapyRecombinant Human Serono AIDS-related Growth Hormone wasting, cachexiaMegestrol Acetate Bristol-Myers Squibb Treatment of anorexia assoc.W/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total EnteralNorwich Eaton Diarrhea and Nutrition Pharmaceuticals malabsorptionrelated to AIDS

Additionally, the compounds of the disclosure herein set forth may beused in combination with other HIV entry inhibitors. Examples of suchHIV entry inhibitors are discussed in Drugs of the Future,24(12):1355-1362 (1999); Cell, 9:243-246 (Oct. 29, 1999); and DrugDiscovery Today, 5(5):183-194 (May 2000) and Meanwell, N. A. et al.,“Inhibitors of the entry of HIV into host cells”, Curr. Op. Drug Disc.Dev, 6(4):451-461 (2003). Specifically the compounds can be utilized incombination with other attachment inhibitors, fusion inhibitors, andchemokine receptor antagonists aimed at either the CCR5 or CXCR4coreceptor.

It will be understood that the scope of combinations of the compounds ofthis disclosure with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable but includes, in principle, any combination with anypharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is KALETRA®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thesecombinations may have unexpected effects on limiting the spread anddegree of infection of HIV. Preferred combinations include those withthe following (1) indinavir with efavirenz, and, optionally, AZT and/or3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddIand/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine. (The preparation ofddC, ddI and AZT are also described in EP 0 484 071.)

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

General Chemistry (Methods of Synthesis)

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes (after theAbbreviations).

Abbreviations

One or more of the following abbreviations, most of which areconventional abbreviations well known to those skilled in the art, maybe used throughout the description of the disclosure and the examples:

h=hour(s)rt=room temperaturemol=mole(s)mmol=millimole(s)g=gram(s)mg=milligram(s)mL=milliliter(s)TFA=trifluoroacetic Acid

DCE=1,2-Dichloroethane

CH₂Cl₂=dichloromethaneTPAP=tetrapropylammonium perruthenateTHF=tetrahydrofuranDEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneDMAP=4-dimethylaminopyridineP-EDC=polymer supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideEDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMF=N,N-dimethylformamide Hunig's Base=N,N-diisopropylethylamine

MCPBA=meta-chloroperbenzoic acidazaindole=1H-pyrrolo-pyridine4-azaindole=1H-pyrrolo[3,2-b]pyridine5-azaindole=1H-pyrrolo[3,2-c]pyridine6-azaindole=1H-pyrrolo[2,3-c]pyridine7-azaindole=1H-pyrrolo[2,3-b]pyridinePMB=4-methoxybenzylDDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinoneOTf=trifluoromethanesulfonoxyNMM=4-methylmorpholinePIP-COPh=1-benzoylpiperazineNaHMDS=sodium hexamethyldisilazideEDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimideTMS=trimethylsilylDCM=dichloromethaneDCE=dichloroethaneMeOH=methanolTHF=tetrahydrofuranEtOAc=ethyl acetateLDA=lithium diisopropylamideTMP-Li=2,2,6,6-tetramethylpiperidinyl lithiumDME=dimethoxyethaneDIBALH=diisobutylaluminum hydrideHOBT=1-hydroxybenzotriazoleCBZ=benzyloxycarbonylPCC=pyridinium chlorochromateTBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborateDEBPT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneBOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

Chemistry

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes.

Preparation of Compounds of Formula I

Preparation of template A-CO—CO—Cl and A-CO—CO—OH has been described indetail in WO-00076521, WO-00162255, WO-00204440, WO-02062423,WO-02085301, WO-03068221 and US-2004/0063744.

Standard conditions such as reacting amine with acyl halide 1 (Scheme1a) and carboxyl acid 4 (Scheme 1b) can be used to convert the ketone tothe desired amide products. Some general references of thesemethodologies and directions for use are contained in “ComprehensiveOrganic Transformation” by Richard C. Larock, Wiley-VCH, New York, 1989,972 (Carboxylic acids to amides), 979 (Acid halides to amides).

Scheme 1a depicts a general method for forming an amide fromN-monosubstituted fused diamine 2 and acyl chloride 1. An appropriatebase (from catalytic to an excess amount) selected from sodium hydride,potassium carbonate, triethylamine, DBU, pyridine, DMAP or di-isopropylethyl amine was added into a solution of fused diamine derivative 2 andacyl chloride 1 in an appropriate solvent selected from dichloromethane,chloroform, benzene, toluene, THF, diethyl ether, dioxane, acetone,N,N-dimethylformamide or pyridine at room temperature. Then reaction wascarried out at either room temperature or evaluated temperature up to150° C. over a period of time (30 minutes to 16 hours) to afford amidine3, the structure of Formula I. Some selected references involving suchreactions include a) Indian J. Chem., Sect B 1990, 29, 1077; 2) Chem.Sci. 1998, 53, 1216; 3) Chem. Pharm. Bull. 1992, 40, 1481; 4) Chem.Heterocycl. Compd. 2002, 38, 539.

Alternatively, as shown in Scheme 1b, a N-monosubstituted fused diamine2 can be coupled with an acid 4 using standard amide bond or peptidebond forming coupling reagents. Many reagents for amide bond couplingsare known by an organic chemist skilled in the art and nearly all ofthese are applicable for realizing coupled amide products. Thecombination of EDAC and triethylamine in tetrahydrofuran or BOPCl anddiisopropyl ethyl amine in chloroform have been utilized most frequentlybut DEPBT, or other coupling reagents such as PyBop could be utilized.Another useful coupling condition employs HATU ((a) J. Chem. Soc. ChemComm. 1994, 201; (b) J. Am. Chem. Soc. 1994, 116, 11580). Additionally,DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, representsanother efficient method to form the amide bond and provide compounds ofFormula I. DEPBT is either purchased from Adrich or prepared accordingto the procedure described in Organic Lett., 1999, 1, 91. Typically aninert solvent such as DMF or THF is used but other aprotic solventscould be used.

The N-monosubstituted fused diamines 5 used in Scheme 1a and Scheme 1bmay be prepared by methods described in the Schemes 2-8.

The N-monoaroylation of fused diamine can be carried out by reacting thedianion 6 of a fused diamine 5 with aroyl chloride. A procedure wasdescribed in J. Org. Chem. 1999, 64, 7661 to prepare mono-aroyl diamineby treatment diamine with 2 equivalents of n-butyllithium, followed bythe addition of aroyl chloride at room temperature. Correspondingly, inthis invention by applying the same procedure in using a fused diamine 5instead, N-monoaroylated spiro diamine can be prepared by treating fuseddiamine 5 with 2 equivalents of n-butyllithium, prior to the addition ofaroyl chloride.

A fused diamine 5 can also be pretreated with 1 eq. of 9-BBN to form acomplex 8 at room temperature in THF, ether, hexane, benzene or CH₂Cl₂.Subsequent reaction between the complex 8 and acyl chloride leads toformation of structure 9 after aqueous workup. A general procedure forthe selective mono-acylation of symmetrical diamines via priorpomplexation with boron can be found in Org. Lett. 2003, 5, 3399.

Alternatively, a N-Boc fused diamine 10 can react with either acylhalide or carboxylic acid via the processes described in Scheme 1a andScheme 1b to acylate the free nitrogen of compound 10, which affordscompound 11. A well established deprotection of Boc group of compound 11under acidic solution could provide acyl fused diamine 9. TFA and HClare the typical acids used for this deprotection, while the mostcommonly used solvents are ether and dichloromethane or the TFA itself,but other acidic agents and solvents could be used. Some selectedreferences involving such reactions include 1) Bioorg. Med. Chem. Lett.1996, 6, 2777; 2) Zh. Org. Khim. 1996, 32, 1010; 3) J. Fluorine Chem.1996, 76, 177; 4) Synth. Commun. 1996, 26, 3549; 5) J. Heterocycl. Chem.1994, 31, 841; 6) J. Org. Chem. 1964, 29, 794.

An excess of fused diamine 5 (5-10 eq.) can be added to a solution ofhalo electrophile 12 (e.g., 5-chloro-1-phenyl-1H-tetrazole) in THF,dioxane, benzene, toluenen, DMSO or DMF. The reaction can be run for 2to 120 hours at room temperature or 150° C. to furnish structure 13. Thereactions can be carried out with or without base or catalyst. A basecan be selected from Et₃N, iPr₂NEt, NaH, KH, BuLi, Li₂CO₃, Na₂CO₃,K₂CO₃, Cs₂CO₃, K₃PO₄, K₂HPO₄, KH₂PO₄, LiHMDS, NaHMDS, KHMDS. A catalystcan be a species containing a metal such as Cu, Pd, Ni or Pt.

Structure 13 can be also synthesized from a N-Boc fused diamine 10. Byusing the same procedure of Scheme 5, N-Boc fused diamine 10 reacts withhalide 12 to give N,N-disubstituted fused diamine 14. Final de-Boc ofcompound 14 using the condition described in Scheme 4 givesN-mono-substituted fused diamine 15.

The N-Boc fused diamine 10 can also react with a N,N-disubstitutedcarbamic chloride 16 with or without a base at room temperature or 150°C. to provide structure 17. The solvent can be selected from THF,dioxane, DMF, benzene, ether, and CH₂Cl₂. The base can be selected fromEt₃N, iPr₂NEt, NaH, KH, BuLi, Li₂CO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, K₃PO₄,K₂HPO₄, KH₂PO₄, LiHMDS, NaHMDS, and KHMDS. Sequential removal of Bocgroup from structure 17, applying the condition described in Scheme 4,leads to the formation of structure 18. In Scheme 7, R¹⁰¹ and R¹⁰² cannot be hydrogen.

The structure 10 can also react with di(1H-imidazol-1-yl)methanone 19,followed by an addition of amine 20 to give intermediate 17. Then,de-Boc reaction will give the desired N-mono substituted fused diamine18. In Scheme 8, R¹⁰¹ or R¹⁰² or both can be hydrogen.

Reaction conditions and methods given in the specific examples arebroadly applicable to compounds with other substitution and to othertransformations in this application.

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormula I as described generally above. These examples are illustrativeonly and are not intended to limit the disclosure in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Chemistry Experimental Typical Procedures and Characterization ofSelected Examples

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d6 (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

HPLC Method (i.e., Compound Isolation)

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL)and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLCsystem.

Preparation of Intermediates Synthesis of2-(1-phenyl-1H-tetrazol-5-yl)octahydropyrrolo[3,4-c]pyrrole

Step 1: Et₃N (5 mL) was added into a solution of tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1 g) and5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture washeated to 115° C. for 24 hours. The reaction was quenched with water (50mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic phase was dried over MgSO₄ and concentrated to give a residuewhich was purified by silica gel chromatography to give tert-butyl5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

tert-butyl 5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate MS (M + H)⁺ Calcd.   357.2 MS (M + H)⁺Observ.   357.3 Retention Time 1.77 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water -90% Methanol-0.1% TFA Start% B  0 Final % B 100 Gradient Time 2 min Flow Rate 4 mL/min Wavelength220 Solvent Pair Water - Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 30mm S5

Step 2: tert-butyl5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(100 mg) was dissolved in 10% TFA solution in CH₂Cl₂ (10 mL). Thereaction was stirred at room temperature for 24 hours. After removal ofsolvents, the residue, crude2-(1-phenyl-1H-tetrazol-5-yl)octahydropyrrolo[3,4-c]pyrrole, was used inthe further reactions without purification.

Synthesis of (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(phenyl)methanone

Step 1: Et₃N (0.5 mL) was added into a solution of tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.2 g) and benzoylchloride (0.11 mL) in THF (10 mL). The mixture was heated to 115° C. for24 hours. The reaction was quenched with water (10 mL). The aqueouslayer was extracted with EtOAc (3×10 mL). The combined organic phase wasdried over MgSO₄ and concentrated to give a residue which was purifiedby silica gel chromatography to give tert-butyl5-benzoylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

tert-butyl 5-benzoylhexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate MS(M + Na)⁺ Calcd.   339.2 MS (M + Na)⁺ Observ.   339.4 Retention Time1.86 min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA SolventB 10% Water -90% Methanol-0.1% TFA Start % B  0 Final % B 100 GradientTime 2 min Flow Rate 4 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 30 mm S5

Step 2: tert-butyl5-benzoylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg) wasdissolved in 10% TFA solution in CH₂Cl₂ (10 mL). The reaction wasstirred at room temperature for 24 hours. After removal of solvents, theresidue, (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(phenyl)methanone, wasused in the further reactions without purification.

Synthesis of Main Compounds Preparation of Compound 1001,1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethane-1,2-dioneand Compound 1002,1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethane-1,2-dione

2-Keto acid (1 eq.), fused bicyclic diamine agent (1-5 eq.),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) orO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1-5 eq.) or(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU) (1-5 eq.) and Hunig's Base or N-methylmorpholine (1-100 eq.) were combined in THF or DMF. The mixture wasstirred at room temperature or 115° C. for 17 hours. THF or DMF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and saturated NaHCO₃ aqueous solution.The aqueous layer was extracted with ethyl acetate. The organic phasewas combined and dried over anhydrous MgSO₄. Concentration in vacuoprovided a crude product, which was purified by tritaration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC System.

MS (M + H)⁺ Calcd. 514.2 MS (M + H)⁺ Observ. 514.3 Retention Time 1.82min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B10% Water -90% Methanol-0.1% TFA Start % B  0 Final % B 100 GradientTime   2 min Flow Rate   4 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

MS (M + H)⁺ Calcd. 540.2 MS (M + H)⁺ Observ. 540.4 Retention Time 1.67min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B10% Water -90% Methanol-0.1% TFA Start % B  0 Final % B 100 GradientTime   2 min Flow Rate   4 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10The Following Methods were Used to Prepare Compounds 2001-2006.

Analytical HPLC Method:

Waters Xbridge 2.1×50 mm 5 um C18, A=5:95 ACN:Water; B=95:5 ACN:Water;Modifier=10 mM NH₄OAc. 0.00 min=0% B, 2.0 min=100% B, 3.0 min=100% B,3.05 min=0% B, 3.5 min=0% B, Flow rate=1 mL/min

The general procedures below pertain to the experimental procedure forlibrary compounds.

2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (1 eq.) was dissolved in DMF and followed by adding DIPEA (3 eq.)and TBTU or HATU (1.1 eq) in DMF (1 mL). The solution then was addedinto a pre-weighed amine (1 eq.). Initial analysis by LC-MS after 3hours indicated that reactions were nearly complete. Reactions wereallowed to remain on the shaker overnight at room temperature. Allsamples were transferred into a plate and purified by HPLC.

2-(4-Methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (1 eq.) was dissolved in DMF and followed by adding DIPEA (3 eq.)and TBTU or HATU (1.1 eq) in DMF (1 mL). The solution then was addedinto a pre-weighed amine (1 eq.). Initial analysis by LC-MS after 3hours indicated that reactions were nearly complete. Reactions wereallowed to remain on the shaker overnight at room temperature. Allsamples were transferred into a plate and purified by HPLC.

MS MS Cmpd (M + H)⁺ (M + H)⁺ RT # Structure Calcd. Observ. (min) 2001

486.2 486.2 1.63 2002

396.2 396.1 1.02 2003

460.2 460.1 1.56 2004

370.1 370.1 1.1  2005

474.2 474.2 1.45 2006

500.2 500.3 5.25

Preparation of Compound 3001,5-(2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)-N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamideand Compound 3002,5-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)-N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

2-Keto amide (1 eq.), carbamyl chloride (1-5 eq.) and Hunig's Base orEt₃N (1-100 eq.) were combined in THF or DMF. The mixture was stirred atroom temperature or 115° C. for 17 hours. THF or DMF was removed viaevaporation at reduced pressure and the residue was partitioned betweenethyl acetate and saturated NaHCO₃ aqueous solution. The aqueous layerwas extracted with ethyl acetate. The organic phase was combined anddried over anhydrous MgSO₄. Concentration in vacuo provided a crudeproduct, which was purified by tritaration, or recrystallization, orsilica gel column chromatography, or Shimadzu automated preparative HPLCSystem.

MS (M + H)⁺ Calcd. 441.2 MS (M + H)⁺ Observ. 441.0 Retention Time 1.70min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B10% Water -90% Methanol-0.1% TFA Start % B  0 Final % B 100 GradientTime   2 min Flow Rate   4 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

MS (M + H)⁺ Calcd. 467.2 MS (M + H)⁺ Observ. 467.0 Retention Time 1.62min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B10% Water -90% Methanol-0.1% TFA Start % B  0 Final % B 100 GradientTime   2 min Flow Rate   4 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

Biology Data for the Examples

“μM” means micromolar;

“mL” means milliliter;

“μl” means microliter;

“mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Table 1 are described below.

Cells:

Virus Production

Human embryonic Kidney cell line, 293T (HEK 293T), was propagated inDulbecco's Modified Eagle Medium (Invitrogen, Carlsbad, Calif.)containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.). Thehuman T-cell leukemia cell MT2 (AIDS Research and Reference ReagentProgram, Cat. 237) was propagated in RPMI 1640 (Invitrogen, Carlsbad,Calif.) containing 10% fetal bovine serum (FBS, Hyclone, Logan, Utah)

Virus Infection

Single-round infectious reporter virus was produced by co-transfectingHEK 293T cells with plasmide expressing the HIV-1 LAI envelope alongwith a plasmid containing an HIV-1 LAI proviral cDNA with the envelopegene replaced by a firefly luciferase reporter gene (Chen et al, Ref41). Transfections were performed using lipofectAMINE PLUS reagent asdescribed by the manufacturer (Invitrogen, Carlsbad, Calif.).

Experimental Procedure

-   1. MT2 cells were plated in black, 384 well plates at a cell density    of 5×10³ cells per well in 25 μl RPMI 1640 containing 10% FBS.-   2. Compound (diluted in dimethylsulfoxide and growth medium) was    added to cells at 12.5 μl/well, so that the final assay    concentration would be ≦50 nM.-   3. 12.5 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle Medium was added to the plated cells and compound at    an approximate multiplicity of infection (MOI) of 0.01, resulting in    a final volume of 50 μl per well.-   4. Virus-infected cells were incubated at 37 degrees Celsius, in a    CO₂ incubator, and harvested 72 h after infection.-   5. Viral infection was monitored by measuring luciferase expression    in the infected cells using a luciferase reporter gene assay kit    (Steady-Glo, Promega, Madison, Wis.) as described by the    manufacturer. Luciferase activity was then quantified by measuring    luminescence using an EnVision Multilabel Plate Readers    (PerkinElmer, Waltham, Mass.).-   6. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.-   7. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of this disclosure. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four parameter logistic model (model 205).    The EC₅₀ data for the compounds is shown in Table 2. Table 1 is the    key for the data in Table 2.

TABLE 1 Biological Data Key for EC₅₀s Compounds with EC₅₀s > 0.5 μMCompounds with EC₅₀ < 0.5 μM Group B Group A

TABLE 2 EC₅₀ Compd. Group from Number Structure Table 1 1001

A 1002

1.41 nM A 2001

A 2003

B 2005

A 2006

0.68 nM A 3001

A 3002

A

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the following examples and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A compound of Formula I, includingpharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

wherein a, b, c, d and e are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A²,C(O)R⁷, C(O)NR⁵⁵R⁵⁶, B, Q, and E; B is selected from the groupconsisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹, aryl, heteroaryl,heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷, XR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may containfrom 1 to 2 heteroatoms in the ring skeleton and which may be fused to abenzene or pyridine ring; Q is selected from the group consisting of(C₁₋₆)alkyl and (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and(C₂₋₆)alkenyl are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group consisting of C(O)NR⁵⁵R⁵⁶, hydroxy, cyano andXR⁵⁷; E is selected from the group consisting of (C₁₋₆)alkyl and(C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms; F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine; R⁷ is selected from the groupconsisting of aryl, heteroaryl, and heteroalicyclic; wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or with from one to three same ordifferent substituents selected from the group F; wherein for R⁷, R⁸,R^(8a), R^(8b) aryl is phenyl; heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for mono cyclic systems and up to10 atoms in a bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is selected from the group consisting ofaziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; R⁸ isselected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; R^(8a) is a member selected from the groupconsisting of aryl, heteroaryl, and heteroalicyclic; wherein each memberis independently optionally substituted with one to six same ordifferent halogens or from one to five same or different substituentsselected from the group F; R^(8b) is selected from the group consistingof hydrogen, (C₁₋₆)alkyl and phenyl; X is selected from the groupconsisting of NH or NCH₃, O, and S; R⁴⁰ and R⁴¹ are independentlyselected from the group consisting of (a) hydrogen; (b) (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl substituted with one to three same or differenthalogens or from one to two same or different substituents selected fromthe group F or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl, heteroaryl orheteroalicyclic; or R⁴⁰ and R⁴¹ taken together with the nitrogen towhich they are attached form a member selected from the group consistingof aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine,piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group F; wherein for R⁴⁰ and R⁴¹ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹ is notselected from groups (a) or (b); R⁴² and R⁴³ are independently selectedfrom the group consisting of hydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R⁴² and R⁴³taken together with the nitrogen to which they are attached form amember selected from the group consisting of aziridine, azetidine,pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, andmorpholine; and wherein said (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group G ordifferent functional groups: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 6 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is a member selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; R⁴⁶ isselected from the group consisting of H, phenyl, aryl, heteroaryl and(C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶; R⁴⁷ is selected from the groupconsisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and(C₁₋₆)alkyl; R⁴⁸ and R⁴⁹ are independently selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl; R⁵⁰ isselected from the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,and benzyl; wherein each of said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl andbenzyl are optionally substituted with one to three same or different(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl R⁵⁴ is selected from the groupconsisting of hydrogen and (C₁₋₆)alkyl; R^(54′) is (C₁₋₆)alkyl; R⁵⁵ andR⁵⁶ are independently selected from the group consisting of hydrogen and(C₁₋₆)alkyl; and R⁵⁷ is selected from the group consisting of hydrogen,(C₁₋₆)alkyl, aryl, heteroaryl; and A¹ and A² are independently selectedfrom hydrogen, (C₁₋₆)alkyl, aryl, heteroaryl, SO2D¹, SO2ND²D³, COD⁴,COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶, COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or they can conjointo form a ring structure; D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, andD¹¹ are each independently selected from the group consisting of H,C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl,phenyl, heteroaryl, C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl isselected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl,oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyland triazolyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₂₀ alkenyl or the carbon-carbontriple bond of said C₃-C₂₀ alkynyl are not the point of attachment tothe nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹, D¹⁰, and D¹¹ is attached;wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀ amide and C₃-C₅₀ ether isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,peroxide and steroid, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; K is selected from the groupof

P is selected form Ar or J; Ar is selected from the group consisting ofphenyl and heteroaryl; wherein said phenyl and heteroaryl are eachindependently optionally substituted with one to three same or differentmembers selected from the group Ar—I; and heteroaryl is selected fromthe group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl,benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyland triazolyl; Ar—I is selected from the group consisting of(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, primary amine,secondary amine, tertiary amine, nitro, thiol, thioether, alcohol,ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone,sulfonamide, sulfamide, oxime and hydrazine, among which ether,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;wherein said (C₁₋₆)alkyl, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl is optionallysubstituted with one to three same or different of the followingfunctionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, oxime and hydrazine, amongwhich ether, thioether, secondary amine, tertiary amine, ammonium,ester, ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; J is selected from the group consisting of H, C₁-C₃₀ alkyl,C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl,aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine,C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether,C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide,C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclicsulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea,C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀guanidine, and C₃-C₃₀ cyclic guanidine; aryl or heteroaryl is selectedfrom the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl,oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl,triazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl,indolyl, azaindolyl, indazolyl, azaindazolyl, benzoisoxazolyl,azabenzoisoxazolyl, benzoisothiazole, azabenzothiazolyl; wherein saidC₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀ bicycloalkyl, C₅-C₃₀tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀ alkenyl, C₄-C₃₀cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀ tricycloalkenyl, C₉-C₃₀tetracycloalkyl, phenyl, aryl, heteroaryl, C₁-C₃₀ amide, C₃-C₃₀ cyclicamide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine, C₂-C₃₀ ester, C₃-C₃₀ cyclicester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether, C₁-C₃₀ sulfonamide, C₃-C₃₀cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀ cyclic sulfone, C₂-C₃₀sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acyl sulfamide, C₃-C₃₀ acylsulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea, C₂-C₃₀ amidine, C₃-C₃₀cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀ cyclic guanidine isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,and peroxide, among which ether, peroxide, thioether, secondary amine,tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; Z is selected from the groupconsisting of phenyl, C₅-C₇ monocyclic heteroaryl, C₉-C₁₀ bicyclic aryl,C₉-C₁₀ bicyclic heteroaryl, C₄-C₇ heteroalicyclic, and C₅-C₇ cycloalkylwherein said heteroaryl or heteroalicyclic contains from 1 to 4heteroatoms selected from O, N, and S and with the proviso when Z is abicyclic heteroaryl both R and Z are attached to a common ring whereinsaid aryl, heteroaryl, and heteroalicyclic are optionally substitutedwith one to three same or different halogens or from one to three sameor different substituents selected from oxo, hydroxyl, C₁-C₆alkyl,—NR¹⁰¹R¹⁰², —OC₁—C₃ alkyl, —S—R_(1,)—S(O)₂R_(1,) CF_(3,) CN; whereinsaid C₁-C₆ alkyl can be optionally substituted with Group B; I₁, I₂, I₃,I₄, I₅, I₆, I₇, I₈, I₉, and I₁₀ are each independently selected from thegroup consisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆) alkenyl,(C₄₋₆) cycloalkenyl, (C₂₋₆) alkynyl, CR⁸¹R⁸²OR⁸³, COR⁸⁴, COOR⁸⁵, orCONR⁸⁶R⁸⁷; wherein each of said alkyl and cycloalkyl being optionallysubstituted with one to three same or different cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl; R⁸¹, R⁸², R⁸³, R⁸⁴,R⁸⁵, R⁸⁶, and R⁸⁷ are each independently selected from the groupconsisting of H, (C₁₋₆)alkyl, (C₃₋₆) cycloalkyl, (C₂₋₆) alkenyl, (C₄₋₆)cycloalkenyl, (C₂₋₆) alkynyl; and wherein R¹⁰¹ and R¹⁰² are selectedfrom the group consisting of H, C₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl, aryl, heteroaryl,C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine,C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether,C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acylsulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea,C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀cyclic guanidine; aryl or heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl, triazolyl, naphthalenyl, quinolinyl,isoquinolinyl, quinoxalinyl, indolyl, azaindolyl, indazolyl,azaindazolyl, benzoisoxazolyl, azabenzoisoxazolyl, benzoisothiazole,azabenzothiazolyl; wherein said C₁-C₃₀ alkyl, C₃-C₃₀ cycloalkyl, C₄-C₃₀bicycloalkyl, C₅-C₃₀ tricycloalkyl, C₆-C₃₀ tetracycloalkyl, C₃-C₃₀alkenyl, C₄-C₃₀ cycloalkenyl, C₅-C₃₀ bicycloalkenyl, C₇-C₃₀tricycloalkenyl, C₉-C₃₀ tetracycloalkyl, phenyl, aryl, heteroaryl,C₁-C₃₀ amide, C₃-C₃₀ cyclic amide, C₁-C₃₀ amine, C₃-C₃₀ cyclic amine,C₂-C₃₀ ester, C₃-C₃₀ cyclic ester, C₂-C₃₀ ether, C₃-C₃₀ cyclic ether,C₁-C₃₀ sulfonamide, C₃-C₃₀ cyclic sulfonamide, C₂-C₃₀ sulfone, C₃-C₃₀cyclic sulfone, C₂-C₃₀ sulfamide, C₃-C₃₀ cyclic sulfamide, C₂-C₃₀ acylsulfamide, C₃-C₃₀ acyl sulfamide, C₂-C₃₀ urea, C₃-C₃₀ cyclic urea,C₂-C₃₀ amidine, C₃-C₃₀ cyclic amidine, C₂-C₃₀ guanidine, and C₃-C₃₀cyclic guanidine is optionally substituted with one to three same ordifferent of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, and peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic.
 2. A compound which is selected from

including pharmaceutically acceptable salts thereof.
 3. The compoundwhich is selected from:

including pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition which comprises an antiviral effective amount of one or moreof the compounds of Formula I as claimed in claim 1, together with oneor more pharmaceutically acceptable carriers, excipients or diluents. 5.A pharmaceutical composition which comprises an antiviral effectiveamount of one or more of the compounds of Formula I as claimed in claim2, together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 6. A pharmaceutical composition which comprisesan antiviral effective amount of one or more of the compounds of FormulaI as claimed in claim 3, together with one or more pharmaceuticallyacceptable carriers, excipients or diluents.
 7. A method for treating amammal infected with HIV comprising administering to said mammal anantiviral effective amount of a compound of Formula I as claimed inclaim 1, and one or more pharmaceutically acceptable carriers,excipients or diluents.
 8. A method for treating a mammal infected withHIV comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I as claimed in claim 2, and one or morepharmaceutically acceptable carriers, excipients or diluents.
 9. Amethod for treating a mammal infected with HIV comprising administeringto said mammal an antiviral effective amount of a compound of Formula Ias claimed in claim 3, and one or more pharmaceutically acceptablecarriers, excipients or diluents.